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Synthesis and Photochemical Activity of Designed Enediynes Graham B. Jones,* Justin M. Wright, Gary Plourde, II, Ajay D. Purohit, Justin K. Wyatt, George Hynd, and Farid Fouad Bioorganic and Medicinal Chemistry Laboratories Department of Chemistry, Northeastern UniVersity Boston, Massachusetts, 02115 ReceiVed March 2, 2000 ReVised Manuscript ReceiVed August 23, 2000 The enediynes are a growing class of antitumor agents, with spectacular biological profiles.1 Nearly 20 discrete enediynes have been discovered, and clinical trials of a number of these are ongoing.2 While the in vitro and in vivo effectiveness of enediynes against certain cancers is unquestioned, the exact mechanism(s) of biological activity remains to be fully resolved. Enediynes per se are biologically inactive, but undergo cycloaromatization reactions which give rise to cytotoxic diyl radicals, which are capable of inducing DNA strand scission at low concentration.1 Depending on local environment, however, it is also possible for other events to occur. One potential class of targets is proteins.3 Excepting water, proteins are the most abundant constituents of cells and extracellular fluids by weight. We recently demonstrated that simple amino acids are viable targets for diyl radicals, resulting in both degradation and dimerization via intermediate carbon centered amino acyl radicals.4 Conventionally, the controlled degradation of proteins is often accomplished through affinity cleavage systems, typically containing a metal-redox center tethered to an entity recognized by the protein of interest.5 Application of enediynes for this purpose could be an attractive proposition but would require two conditions be met: (i) the system must have affinity for a protein of interest and (ii) the enediyne needs to be thermally stable until activated “on demand”. An attractive method for activation lies in the photochemical triggering of an otherwise unreactive enediyne. Indeed, examples of the direct “photochemical Bergman” cyclization have been reported.6-9 In most examples studied to date the vinyl moiety of the enediyne is embedded in an arene, and mindful of this restriction, we wished to design a family of alicyclic enediynes 1, and investigate their photochemical activation to diyls 2, as a function of ring strain and electronic effects.10 * Address correspondence to this author. (1) Smith, A. L.; Nicolaou, K. C. J. Med. Chem. 1996, 39, 2103. (2) Xi, Z.; Goldberg, I. DNA Damaging enediyne compounds. In ComprehensiVe Natural Products Chemistry; Barton, D. H. R., Nakanishi, K., Eds.; Pergamon: Oxford, 1999; Vol. 7, p 553. (3) Zein, N.; Solomon, W.; Casazza, A. M.; Kadow, J. F.; Krishnan, B. S.; Tun, M. M.; Vyas, D. M.; Doyle, T. W. Bioorg. Med. Chem. Lett. 1993, 3, 1351. Jones, G. B.; Kilgore, M. W.; Pollenz, R. S.; Li, A.; Mathews, J. E.; Wright, J. M.; Huber, R. S.; Tate, P. L.; Price, T. L.; Sticca, R. P. Bioorg. Med. Chem. Lett. 1996, 6, 1971. (4) Jones, G. B.; Plourde, G.; Wright, J. W. Org. Lett. 2000, 2, 811. Jones, G. B.; Wright, J. M.; Hynd, G.; Wyatt, J. K.; Yancisin, M.; Brown, M. A. Org. Lett. 2000, 2, 1863. (5) Rana, T. M.; Meares, C. F. J. Am. Chem. Soc. 1991, 113, 1859. Hoyer, D.; Cho, H.; Schultz, P. G. J. Am. Chem. Soc. 1990, 112, 3249. Cuenoud, B.; Tarasow, T. M.; Schepartz, A. Tetrahedron Lett. 1992, 33, 895. Hegg, E. L.; Burstyn, J. N. J. Am. Chem. Soc. 1995, 117, 7015. Wu, J.; Perrin, D. M.; Sigman, D. S.; Kaback, H. R. Proc. Nat. Acad. Sci. 1995, 92, 9186. Parac, T. N.; Kostic, N. M. J. Am. Chem. Soc. 1996, 118, 5946. Kumar, C. V.; Buranaprapuk, A. J. Am. Chem. Soc. 1999, 121, 4262. Miyake, R.; Owens, J. T.; Xu, D.; Jackson, W. M.; Meares, C. F. J. Am. Chem. Soc. 1999, 121, 7453. (6) Funk, R. L.; Young, E. R. R.; Williams, R. M.; Flanagan, M. F.; Cecil, T. L. J. Am. Chem. Soc. 1996, 118, 3291. (7) Turro, N. J.; Evenzahav, A.; Nicolaou, K. C. Tetrahedron Lett. 1994, 35, 8089. Evenzahav, A.; Turro, N. J. J. Am. Chem. Soc. 1998, 120, 1835. (8) Ramkumar, D.; Kalpana, M.; Varghese, B.; Sankararaman, S.; Jagadeesh, M. N.; Chandrasekhar, J. J. Org. Chem. 1996, 61, 2247. (9) Kaneko, T.; Takahashi, M.; Hirama, M. Angew. Chem., Int. Ed. 1999, 38, 1267.
Scheme 1. Photochemical Bergman Cycloaromatization
Scheme 2. Synthesis of Alicyclic Photo-Bergman Candidates
Commencing from commercially available acyl chlorides 3, the corresponding diketones 4 were produced via the intermediate Weinreb amides (Scheme 2).11 Low-valent Ti-mediated coupling gave 6 directly, but the yields were variable, in part due to problems recovering product from complex mixtures. Alternatively, conversion to bromides 5 followed by carbenoid coupling gave 6 (n ) 1-5) in good yield on a preparative scale.12 Though stable at room temperature, photochemical Bergman cycloaromatization gave adducts 8 in moderate yield, presumably via diyls 7 (Table 1). As had been found previously, the nature of the hydrogen donor plays an important role in the conversion to arene adduct.7 Thus, although consumption of enediyne was often rapid using 1,4-cyclohexadiene, optimal yields of cycloaromatization products were obtained using 2-propanol, the balance of material typically composed of uncharacterized polymeric byproducts. Evidently ring strain effects play a role in the cycloaromatization, with lower conversion efficiency observed with the C-7 and C-8 analogues despite the appreciable reduction in intramolecular “c-d” distances relative to the six-membered analogue (Table 1).1 Though photo-Bergman cycloaromatization yields are modest, the synthesis of this class of enediynes [4- through 8-membered] is noteworthy and may lead to many new applications in materials and polymer chemistry.13 With a route to photoactivated enediynes secure, we wished to investigate interaction of the intermediate diyl radicals 2 with protein targets, and accordingly sought to prepare a hydrophilic variant, which was capable of recognizing protein architecture. Our design was influenced by the work of Kumar,14 who reported that an alkyl pyrenyl derivative of phenylalanine (Figure 1) recognizes the proteins bovine serum albumin (BSA) and lysozyme, inducing photocleavage following irradiation in the presence of an electron acceptor.14 Molecular modeling studies indicated that arene 14, the expected photocycloaromatization product of enediyne 13 (Scheme 3), bears a close structural resemblance to the reference probe, providing us with a logical candidate for proof-of-principle studies. (10) Schmittel, M.; Kiau, S. Chem. Lett. 1995, 953. Schmittel, M.; Kiau, S. Liebigs Ann./Recl. 1997, 1391. Jones, G. B.; Plourde, G. W. Org. Lett. 2000, 2, 1757. (11) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815. (12) Jones, G. B.; Wright,J. M.; Plourde, G. W., II; Hynd, G.; Huber, R. S.; Mathews, J. E. J. Am. Chem. Soc. 2000, 122, 1937. (13) John, J. A.; Tour, J. M. J. Am. Chem. Soc. 1994, 116, 5011. (14) Kumar, C. V.; Buranaprapuk, A.; Opiteck, G. J.; Moyer, M. B.; Jockusch, S.; Turro, N. J. Proc. Natl. Acad. Sci. 1998, 95, 10361.
10.1021/ja000766z CCC: $19.00 © 2000 American Chemical Society Published on Web 09/23/2000
Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 40, 2000 9873
Table 1. Synthesis and Cycloaromatization of Enediyne 6 entry
n
c-d (Å)a
irradiation (h)b
conversionc
% 8d (based on 6)
1 2 3 4 5 6
2 3 4 4 5 6
4.941 4.284 4.018 4.018 3.947 3.893
3 3 3 12 12 12
100e 97 49 95 70 66
0 (0) 13 (13) 15 (31) 21 (22) 11 (16) 9 (14)
a Equilibrium geometry calculated using PM3 (PC Spartan Pro). Reactions conducted at 0.4 g/L enediyne in 2-propanol in a quartz vessel, irradiated using a 450 W (Hanovia) lamp. c Based on recovered starting material. d Isolated yields. e Decompostion and formation of polymeric adducts ensues in
